Design of an antithrombotic-antihypertensive agent (Wy 27569). Synthesis and evaluation of a series of 2-heteroaryl-substituted dihydropyridines.
An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.
Archibald
J L
JL
Department of Chemistry, Wyeth Research UK, Maidenhead, Berkshire, England.
Bradley
G
G
Opalko
A
A
Ward
T J
TJ
White
J C
JC
Ennis
C
C
Shepperson
N B
NB
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis*; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D000959:Antihypertensive Agents; D004095:Dihydropyridines; D005343:Fibrinolytic Agents; D007093:Imidazoles; C029166:dazoxiben; C059815:Wy 27569; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D009568:Nitrendipine; D013930:Thromboxane-A Synthase